Andrei Leonov

The quantum nature of skyrmions and half-skyrmions in Cu2OSeO3

The Skyrme-particle, the skyrmion, was introduced over half a century ago in the context of dense nuclear matter. But with skyrmions being mathematical objects--special types of topological solitons--they can emerge in much broader contexts. Recently skyrmions were observed in helimagnets, forming nanoscale spin-textures. Extending over length scales much larger than the interatomic spacing, they behave as large, classical objects, yet deep inside they are of quantum nature. Penetrating into their microscopic roots requires a multi-scale approach, spanning the full quantum to classical domain. Here, we achieve this for the first time in the skyrmionic Mott insulator Cu2OSeO3. We show that its magnetic building blocks are strongly fluctuating Cu4 tetrahedra, spawning a continuum theory that culminates in 51 nm large skyrmions, in striking agreement with experiment. One of the further predictions that ensues is the temperature-dependent decay of skyrmions into half-skyrmions.

Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease

Abstract In neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood–brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.

Dynamics of the glycosidic bond: conformational space of lactose.

The dynamics of the glycosidic bond of lactose was studied by a paramagnetic tagging-based NMR technique, which allowed the collection of an unusually large series of NMR data for a single compound. By the use of distance- and orientation-dependent residual dipolar couplings and pseudocontact shifts, the simultaneous fitting of the probabilities of computed conformations and the orientation of the magnetic susceptibility tensor of a series of lanthanide complexes of lactose show that its glycosidic bond samples syn/syn, anti/syn and syn/anti ϕ/ψ regions of the conformational space in water. The analysis indicates a higher reliability of pseudocontact shift data as compared to residual dipolar couplings with the presently available weakly orienting paramagnetic tagging technique. The method presented herein allows for an improved understanding of the dynamic behaviour of oligosaccharides.

The PIP2 binding mode of the C2 domains of rabphilin-3A.

Phosphatidylinositol‐4,5‐bisphosphate (PIP2) is a key player in the neurotransmitter release process. Rabphilin‐3A is a neuronal C2 domain tandem containing protein that is involved in this process. Both its C2 domains (C2A and C2B) are able to bind PIP2. The investigation of the interactions of the two C2 domains with the PIP2 headgroup IP3 (inositol‐1,4,5‐trisphosphate) by NMR showed that a well‐defined binding site can be described on the concave surface of each domain. The binding modes of the two domains are different. The binding of IP3 to the C2A domain is strongly enhanced by Ca2+ and is characterized by a KD of 55 μM in the presence of a saturating concentration of Ca2+ (5 mM). Reciprocally, the binding of IP3 increases the apparent Ca2+‐binding affinity of the C2A domain in agreement with a Target‐Activated Messenger Affinity (TAMA) mechanism. The C2B domain binds IP3 in a Ca2+‐independent fashion with low affinity. These different PIP2 headgroup recognition modes suggest that PIP2 is a target of the C2A domain of rabphilin‐3A while this phospholipid is an effector of the C2B domain.

The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset

]. parkinson’s disease (pD) is characterized by the deposition of aggregated alpha-synuclein (asyn). recent evidence suggests that oligomers formed in the aggregation process constitute the main toxic species causing neurodegeneration. recently, we reported that the oligomer modulator “anle138b” [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole] is capable of prolonging the survival of prion-infected mice and of various animal models of pD [5blocked formation and accumulation of asyn oligomers in the brain, reduced disease-associated motor deficits, and led to prolonged disease-free survival [5 ]. These findings support the following

The Absolute Configuration of (+)‐ and (−)‐erythro‐Mefloquine

The controversy over the absolute configuration of (+)-erythro-mefloquine, the less psychosis-causing enantiomer of the anti-malarial drug Lariam, has been resolved by Mosher ester crystallization. The configuration determined previously by physical methods is correct, whereas the configuration determined by three enantioselective syntheses is wrong.

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.

The C2A-C2B linker defines the high affinity Ca2+ binding mode of rabphilin-3A

The Ca2+ binding properties of C2 domains are essential for the function of their host proteins. We present here the first crystal structures showing an unexpected Ca2+ binding mode of the C2B domain of rabphilin-3A in atomic detail. Acidic residues from the linker region between the C2A and C2B domains of rabphilin-3A interact with the Ca2+-binding region of the C2B domain. Because of these interactions, the coordination sphere of the two bound Ca2+ ions is almost complete. Mutation of these acidic residues to alanine resulted in a 10-fold decrease in the intrinsic Ca2+ binding affinity of the C2B domain. Using NMR spectroscopy, we show that this interaction occurred only in the Ca2+-bound state of the C2B domain. In addition, this Ca2+ binding mode was maintained in the C2 domain tandem fragment. In NMR-based liposome binding assays, the linker was not released upon phospholipid binding. Therefore, this unprecedented Ca2+ binding mode not only shows how a C2 domain increases its intrinsic Ca2+ affinity, but also provides the structural base for an atypical protein-Ca2+-phospholipid binding mode of rabphilin-3A.

Chiral discrimination of amines by anisotropic NMR parameters using chiral polyacrylamide-based gels.

A new chiral alignment medium for dimethyl sulfoxide, methanol, and water as solvents was developed. Because both enantiomers of the gel are available, it is possible to enantiodiscriminate natural products such as strychnine HCl that naturally occurs as single enantiomer. With the two methods of achieving anisotropy, namely stretching and confinement, the degree of alignment can be adjusted, and the director changed from horizontal to vertical. This increases the applicability. Three compounds were enantiodiscriminated on the basis of residual dipolar coupling data: mefloquine HCl, strychnine HCl, and menthylamine HCl. Copyright

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π-electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.